A systematic review and meta-analysis found that sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP1RA) associated with the most favorable cardiorenal outcomes when used as an adjunct with metformin in people with type 2 (T2D) diabetes. These findings were published in Diabetic Medicine.

Publication databases were searched through July 2021 for studies of second-line glucose lowering medications used in adjunct with metformin for their cardiorenal and adverse outcomes. A pairwise meta-analysis and network meta-analysis were carried out using data from 38 trials conducted between 2005 and 2021.

The studies examined SGLT2i (n=14), GLP1RA (n=9), dipeptidyl peptidase-4 inhibitors (DPP-4i; n=9), sulphonylureas (n=8), glitazones (n=4), insulin (n=2), and dopamine-2 agonists (n=1). Most trials (n=26) had a sample size >3000 and most (n=23) had a low risk for bias across all assessed domains.

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The studies comprised 227,497 patients aged mean 63.7 years, 63.5% were men, glycated hemoglobin (HbA1C) was 7.9%, and diabetes had been diagnosed 10.6 years prior.

In the pairwise meta-analysis, SGLT2i was associated with the most favorable outcomes, decreasing risk for 9 cardiovascular and renal outcomes: decline in estimated glomerular filtration rate (eGFR)  (relative risk [RR], 0.59), doubling of serum creatinine (RR, 0.64), renal composite outcomes (RR, 0.64), end-stage renal disease (ESRD; RR, 0.68), acute kidney injury (RR, 0.85), cardiovascular death (RR, 0.86), all-cause mortality (RR, 0.86), hospitalization for heart failure (RR, 0.71), and 3-point major adverse cardiovascular events (MACE; RR, 0.90).

The next-best therapy was GLP1RA with 8 associations: developing macroalbuminuria (RR, 0.77), renal composite outcomes (RR, 0.78), ESRD (RR, 0.84), all stroke (RR, 0.85), non-fatal stroke (RR, 0.85), 3-point MACE (RR, 0.87), cardiovascular death (RR, 0.88), and all-cause mortality (RR, 0.89).

Sulphonylureas decreased risk for the 5 outcomes of ESRD (RR, 0.35), developing macroalbuminuria (RR, 0.70), renal composite outcomes (RR, 0.79), microalbuminuria (RR, 0.92), and progression of albuminuria (RR, 0.92).

DPP-4i reduced risk for developing macroalbuminuria (RR, 0.75) and non-fatal stroke (RR, 0.91) and dopamine-2 agonists, 3-point MACE (RR, 0.46).

For adverse effects, SGLT2i had the most associations with genital infection (RR, 3.67), ketoacidosis (RR, 2.06), amputation (RR, 1.21), and volume depletion (RR, 1.16).

Insulin increased risk for hypoglycemia  (RR, 2.27) and hypoglycemia (RR, 3.187) and glitazones for hypoglycemia (RR, 1.39) and fracture (RR, 1.57). Sulphonylureas were associated with severe hypoglycemia (RR, 1.85), DPP-4i with acute pancreatitis (RR, 1.78), GLP1RA with cholelithiasis or acute cholecystitis (RR, 1.23), and dopamine-2 agonists with overall adverse events (RR, 1.07).

In the network meta-analysis, similar results were observed as in the pairwise meta-analysis.

Researchers acknowledged the network analysis in this study was limited by the small number of trials.

“In conclusion, our study provided high certainty to suggest that SGLT2i and GLP1RA lowered risk for different cardiorenal end points, when used as an adjunct to metformin in people with T2D. SGLT2i also demonstrated benefits in reducing risk for surrogate endpoints for kidney disease progression,” concluded the study authors, adding that additional studies were needed.


Sim R, Chong CW, Loganadan NK, et al. Comparative effectiveness of cardiovascular, renal and safety outcomes of second-line antidiabetic drugs use in people with type 2 diabetes: A systematic review and network meta-analysis of randomised controlled trials. Diabet Med. 2021;39(3):e14780. doi:10.1111/dme.14780